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Patients with rheumatoid arthritis (RA) who were treated with tocilizumab (Actemra) had twice the risk of gastrointestinal perforations than those on tumor necrosis factor (TNF) inhibitors, Swedish researchers reported.

Compared with patients receiving TNF inhibitors, the fully adjusted hazard ratio for gastrointestinal perforation among tocilizumab users was 2.20 (95% CI 1.28-3.79, P=0.0045), according to Andrei Barbulescu, PhD, and colleagues from the Karolinska Institute in Stockholm.

This represented one additional gastrointestinal perforation event for each 451 patient-years of treatment with tocilizumab instead of a TNF inhibitor, the researchers reported online in .

An increased risk of gastrointestinal perforation -- a rare but potentially deadly event -- has been observed among patients with RA. Contributing to this risk are the use of glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs), while treatment with conventional disease-modifying antirheumatic drugs (DMARDs) does not seem to increase the risk.

Uncertainty remains, however, as to whether exposure to biologic agents also influences this risk. There have been reports of perforations occurring among patients receiving etanercept (Enbrel), and the prescribing information for other TNF inhibitors describes this as a potential adverse event. A , however, found no difference in risk between TNF inhibitors and conventional DMARDs.

There are fewer data on risks associated with non-TNF biologics, but a safety signal was noted in early studies of tocilizumab, and reports from and the suggested higher risks with this agent. These studies, however, did not adjust for factors that might influence choice of therapy, such as disease activity or inflammation.

"With differences in outcome definitions, limited statistical power, and lack of data on important confounders in these previous studies, additional evidence is warranted before strong conclusions on the possibly increased risk of gastrointestinal perforations in RA, and specifically with tocilizumab, can be drawn," Barbulescu and co-authors wrote.

To address this, they analyzed data from the Swedish Biologics Register and the National Patient Register from 2009 to 2017, matching RA biologic-treated patients according to age, sex, and geographical location with general population controls. Also included were patients considered bio-naive who had been diagnosed with RA but had not yet started a biologic treatment.

Specific agents included in the analysis were the TNF inhibitors etanercept, infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), as well as rituximab (Rituxan), abatacept (Orencia), and tocilizumab.

The analysis adjusted for multiple covariates including comorbidities, history of gastrointestinal disorders, cardiovascular disease, and infections, as well as disease activity and severity, using inverse probability of treatment weighting. Further adjustments were made for glucocorticoid and NSAID exposure.

Each treatment initiation was considered separately, with the TNF inhibitors being one group, so patients could have multiple initiations if they switched treatments.

The study included 76,304 general population controls, 62,532 patients with RA who were bio-naive, 17,594 treatment initiations with TNF inhibitors, 2,527 initiations of abatacept, 3,552 initiations of rituximab, and 2,377 of tocilizumab. Follow-up times were 5 years for the bio-naive group, 1.2 years for the TNF inhibitor group, 1.3 years for the abatacept group, 2.2 years for the rituximab group, 1.4 years for the tocilizumab group, and 4.4 years for controls.

The age- and sex-standardized incidence rate of lower gastrointestinal tract perforation in the general population was 1.1 (95% CI 1-1.3) per 1,000 person-years. Rates were higher among all RA groups: 1.6 (95% CI 1.5-1.7) per 1,000 for bio-naive patients, 1.8 (95% CI 1.4-3.6) for patients who received TNF inhibitors, 2.0 (95% CI 1.3-5.7) for those who received rituximab, 3.3 (95% CI 1.7-16.6) for those who received abatacept, and 4.5 (95% CI 2.7-10.4) for those who received tocilizumab.

Comparisons of the incidence rates among biologic-treated patients before adjustment found higher rates for the non-TNF biologics, with 2.6 (1.5-4.5) per 1,000 person-years for abatacept, 2.1 (95% CI 1.4-3.2) for rituximab, and 4.1 (95% CI 2.7-6.2) for tocilizumab, compared with 1.6 (95% CI 1.2-2.1) for the TNF inhibitors.

But after full adjustment with inverse probability treatment weighting, neither abatacept nor rituximab had a significantly higher risk compared with the TNF inhibitors, with hazard ratios of 1.07 (95% CI 0.55-2.10, P=0.8341) and 0.89 (95% CI 0.50-1.58, P=0.6980), leaving only tocilizumab with a statistically higher risk of 2.20.

A potential explanation for the increased risk with tocilizumab lies in its mechanism of action, which is inhibition of interleukin (IL)-6. The expression of IL-6 is upregulated with gastrointestinal injury, which is likely to aid in wound healing, and this cytokine also regulates vascular endothelial growth factor, which further contributes to wound healing, the researchers explained. "By blocking IL-6 signaling, tocilizumab may slow down these healing processes."

"The absolute rates remained low, but considering the seriousness of gastrointestinal perforations, even a slightly increased risk warrants caution when using tocilizumab," the team concluded. The prescribing information for the drug states that it should be used with caution in patients at increased risk.

A limitation of the study, the researchers said, was its reliance on healthcare registries for data.

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